The humoral and cell-mediated immune response declines with age in both animals and man. One of the causes for the reduced response is the inability of lymphocytes to transform and proliferate after coming into contact with the antigen. Both thymus-derived lymphocytes (T-cells) and bone marrow-derived lymphocytes (B-cells) are affected as determined by a decrease in the number of antibody-forming progeny generated per immunocompetent unit, a decrease in the mixed lymphocyte reaction and a depressed response to specific mitogens. Recent evidence suggests the relative levels of cyclic-AMP and cyclic-GMP may regulate cell division. It is postulated that the reduced proliferative ability of the old cells is due to age-related changes in the cell membrane which results in a defect in the cyclic-AMP--cyclic-GMP system. Preliminary results indicate that in mitogen-stimulated young spleen cells there is an immediate rise in cyclic-GMP and drop in cyclic-AMP levels. These changes do not occur to the same degree in old cells. Experiments are proposed to separate the T- and B-cells from young and old spleens and measure the change in cyclic nucleotide levels and the activity of adenylate cyclase, guanylate cyclase, and phosphodiesterases after mitogen stimulation. Various agents which alter cyclic-AMP and cyclic- GMP levels will be used to attempt to correct the defect in the old lymphocytes. If the proliferative ability of the old cells can be restored by altering the cyclic nucleotide levels, the ability of the old cells to function in a cell-mediated and humoral response will be tested.